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A bstract   Hematopoietic stem cell (HSC) transplantation (HSCT) for malignancy requires toxic pre‐conditioning to maximize anti‐tumor effects and donor‐HSC engraftment. While this induces bone marrow (BM)‐localized inflammation, how this BM environmental change affects transplanted HSCs in vivo remains largely unknown. We here report that, depending on interval between irradiation and HSCT, residence within lethally irradiated recipient BM compromises donor‐HSC reconstitution ability. Both in vivo and in vitro we demonstrate that, among inflammatory cytokines, TNF‐α plays a role in HSC damage: TNF‐α stimulation leads to accumulation of reactive oxygen species (ROS) in highly purified hematopoietic stem/progenitor cells (HSCs/HSPCs). Transplantation of flow‐cytometry—sorted murine HSCs reveals damaging effects of accumulated ROS on HSCs. Short‐term incubation either with an specific inhibitor of tumor necrosis factor receptor 1 signaling or an antioxidant  N ‐acetyl‐L‐cysteine (NAC) prevents TNF‐α‐mediated ROS accumulation in HSCs. Importantly, pre‐transplantation exposure to NAC successfully demonstrats protective effects in inflammatory BM on graft‐HSCs, exhibiting better reconstitution capability than that of nonprotected control grafts. We thus suggest that in vivo protection of graft‐HSCs from BM inflammation is a feasible and attractive approach, which may lead to improved hematopoietic reconstitution kinetics in transplantation with myeloablative conditioning that inevitably causes inflammation in recipient BM. S tem  C ells   2017;35:989–1002

Pre‐Transplantation Blockade of TNF‐α‐Mediated Oxygen Species Accumulation Protects Hematopoietic Stem Cells